19-49864364-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007254.4(PNKP):c.538C>A(p.Arg180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,613,998 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 3 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.85

Publications

7 publications found

Variant links:

Genes affected

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP Gene-Disease associations (from GenCC):

ataxia - oculomotor apraxia type 4
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PNKP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010188431).

BP6

Variant 19-49864364-G-T is Benign according to our data. Variant chr19-49864364-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00307 (468/152280) while in subpopulation AFR AF = 0.011 (458/41556). AF 95% confidence interval is 0.0102. There are 6 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.538C>A	p.Arg180Ser	missense	Exon 5 of 17	NP_009185.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKP	ENST00000322344.8	TSL:1 MANE Select	c.538C>A	p.Arg180Ser	missense	Exon 5 of 17	ENSP00000323511.2	Q96T60-1
PNKP	ENST00000596014.5	TSL:1	c.538C>A	p.Arg180Ser	missense	Exon 4 of 16	ENSP00000472300.1	Q96T60-1
PNKP	ENST00000593946.5	TSL:1	n.*465C>A		non_coding_transcript_exon	Exon 4 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

466

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000847

AC:

213

AN:

251444

AF XY:

0.000640

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000314

AC:

459

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

209

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0124

AC:

416

AN:

33476

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111874

Other (OTH)

AF:

0.000480

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00307

AC:

468

AN:

152280

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0110

AC:

458

AN:

41556

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.00380

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000980

AC:

119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Microcephaly, seizures, and developmental delay (2)

Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)

Developmental and epileptic encephalopathy, 12 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

PhyloP100

1.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

REVEL

Benign

0.053

Sift

Benign

0.079

Sift4G

Benign

0.084

Polyphen

0.018

Vest4

0.35

MVP

0.65

MPC

0.11

ClinPred

0.018

GERP RS

3.8

Varity_R

0.20

gMVP

0.49

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over